The invention relates generally to compounds active against viral diseases and, more specifically to bicyclic carbohydrate compounds that are useful in the prophylaxis and treatment of diseases caused by the alphaherpesvirina cytomegalovirus.
Cytomegalovirus (CMV) is the largest human herpes virus, and there is only one serotype. As with animal CMVs it is species specific; humans are the natural hosts and animal CMVs do not infect humans. The name refers to the multinucleated cells, which together with the intranuclear inclusions, are characteristic responses to infection with this virus. Transmission is via saliva, and CMVs were originally called ‘salivary gland’ viruses. Urine is an additional source of infection in children, and in infected pregnant women the virus can spread via the blood to the placenta and fetus. Semen and cervical secretions may also contain virus and it can therefore be spread by sexual contact. It is often present in milk in small quantities, but this is of doubtful significance in transmission. In hospitals it can be transmitted by blood transfusion and organ transplants. CMV infections are often asymptomatic, but can reactivate and cause disease when CMI (cell mediated immune response) defenses are impaired. After clinical silent infection of unknown cells in the upper respiratory tract, CMV spreads locally to lymphoid tissues and then systemically in circulating lymphocytes and monocytes to involve lymph nodes and the spleen. The infection then localizes in epithelial cells in salivary glands and kidney tubules, and in cervix, testes and epididymis, from where the virus is shed to the outside world (Table 1).
TABLE 1Cytomegalovirus infectionsSite of infectionResultCommentSalivary glandsSalivary transmissionImportance of kissing andcontaminated handsTubular epithe-Virus in urineProbable role of transmissionlium of kidneyCervix/Testis/Sexual transmissionUp to 107 infectious doses/mlepididymisof semen in an acutelyinfected maleLymphocytes/Virus spread throughProbable site of persistentMacrophagesbody via infected cellsinfectionMononucleosis mayoccurImmunosuppressiveeffectPlacenta/FetusCongenitalGreatest damage in fetus afterabnormalitiesprimary maternal infectionrather than reactivation
Infected cells may be multinucleated or bear intranuclear inclusions, but pathologic changes are minor and infection is generally asymptomatic. In young adults, a glandular fever type illness can occur, but without heterophil antibodies. There is fever and lethargy, and abnormal lymphocytes and mononucleosis in blood smears. The virus inhibits T cell responses and there is a temporary reduction in their immune reactivity to other antigens. Although specific antibodies and CMI responses are generated, these fail to clear the virus, which often continues to be shed in saliva and urine for many months. The infection is, however, eventually controlled by CMI mechanisms, although infected cells remain in the body throughout life and can be a source of reactivation and disease when CMI defenses are impaired. CMV owes its success in our species to its ability to evade immune defenses (Cann A. J. (1997) Principles of Molecular Virology. Second Edition. Academic Press, San Diego, pp. 65–67; Mims C., Playfair J., Roitt I., Wakelin D. and Williams R. (1998) Medicinal Microbiology. Second Edition. Mosby International Limited, pp.347–348).
Ganciclovir is an anti-CMV drug that works by inhibiting CMV's DNA polymerase enzyme. It can prevent CMV from reproducing and infecting new cells, but it cannot eliminate it from the body. Ganciclovir is manufactured by Roche under the trade name Cymevene. In the US its trade name is Cytovene. Ganciclovir now comes in several formulations: oral, intravenous and intravitreal (into the eye). It is either given intravenously on a long-term basis through a catheter or in a pill form. In the case of administration by catheter, one end of a tube is surgically inserted into a large vein in the chest, the other end of the tube remains outside the chest or has an injectable port just under the skin. Although slightly less efficient, an oral form of ganciclovir is also approved by the FDA for prevention and maintenance treatment of CMV.
Unfortunately, ganciclovir also suppresses bone-marrow production of the white blood cells called neutrophils. This condition is called neutropenia. People taking ganciclovir require close monitoring to ensure blood disorders are promptly detected. It can also harm the kidneys, reduce testosterone levels, and cause nausea, vomiting, diarrhea and rash. More than 10% of IV ganciclovir recipients have to stop treatment because of these side effects. In addition, the development of strains of CMV that are resistant to ganciclovir has been reported. These do not seem to develop any faster with oral ganciclovir than with the intravenous formulation (www.aidsmap.com).
Alternative compounds with activity against herpes viruses such as cytomegalovirus are needed.